AspergillusOne-Health
Deciphering of azole resistance in Aspergillus fungi through a One Health approach
The AspergillusOne-Health project faces 4 major bolts: (i) The specific environmental sources and the extent of the problem are unknown in France; (ii) in clinical practice, there is few information about the putative predisposition of patient’s underlying pulmonary disease and on avian specificities; (iii) at the pathogen level, the population structure and fitness cost of resistance emergence is unknown and finally (iv) a large relevant multidisciplinary team is necessary to conduct an optimal One health approach.
The principal objective of the AspergillusOne-Health prospective study is to identify hotspots as possible sources for selection and reservoirs of azole-resistant A. fumigatus in the environment. The secondary objectives are i) to determine the prevalence of environmental azole-resistant Aspergillus in patients with various pulmonary diseases (WP1-task1) and the presence of this phenomenon in avian farms and hatcheries (WP1-task2). The environment component of the One-Health approach will target patients’ home and extra-domicile, avian farm environment, agricultural (cereals, market -garden, vineyards,...) and sawmills soil for fungi isolation, and soils for fungicide detection (WP1-task3). Moreover, more information about Aspergillus population (WP2-task1), including resistant cryptic species, is required to strengthen ecologic knowledge on this genus. Indeed, within other taxonomic sections, than Fumigati, acquired resistance to azole treatments has been observed but environmental origin has not been investigated. ii) to model spread of resistance. Spatial dispersion of Aspergillus section Fumigati has to be evaluated in regard to resistance levels and typing. This data has to be correlated to fungicide detection in soil (this project) and air (AirPL database) and water (DREAL database) (WP2-task2) with the objective to model the emergence and spread of azole resistance (WP2-task3). Another secondary objective is iii) to identify conditions which could promote the persistence of resistant Aspergillus in the environment and in the patient. For that, the impact of resistance traits on Aspergillus fitness cost will be evaluated in conditions mimicking some environmental parameters such as metal ions, pH, temperature and host interaction conditions (WP3). Although it deals with all respiratory pathologies, the fact that the Nantes University Hospital is one of the two Cystic Fibrosis Resource and Competence centres in France, and that the Pays de la Loire region is the second largest poultry and hatching eggs producer and one of the highest users of pesticides (including azoles) in France, this region was an obvious strategic choice for this project
Période du projet :
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Investigateur principal :
Patrice Le Pape ; Université de Nantes UR1155 IICiMEd
Membre(s) SESSTIM du projet :
Commanditaires :
ANR
Partenaires :
Université de Nantes UR1155 IICiMEd
Site Web dédié au projet :
https://anr.fr/Projet-ANR-22-CE35-0013
Problématique:
Aspergillus fumigatus is the most common etiological agent involved in aspergillosis clinical manifestations. It is estimated that this pathogen is responsible for over half a million deaths per year worldwide. The recent increase in the number of azole drug resistant A. fumigatus isolates from environmental and clinical specimens is of concern to microbiologists and clinicians due to life-threatening treatment failures. Systematic azole-resistance surveillance is a new priority, advocated by ECDC and WHO 2020 recommendations and in January 2021, CDC called for proposals to estimate prevalence of antifungal-resistant A. fumigatus in low- and middle-income countries. Sterol 14α-demethylation inhibitors (DMIs) are the most widely used chemical family to control fungal pathogens in humans, animals and also dominate the agricultural fungicide market since their introduction in the 1970s. The azole resistance in Aspergillus could therefore benefit from a One health approach.
Méthode :
The project is built in 3 scientific work packages (WP1-WP3) which will be supervised by a project management work package (WP0) throughout the duration of the research project and finally a work package (WP4) for the dissemination of the results both to the specialised scientific community and to the citizens, general public and stakeholders. Scientific risks and fall-back solutions were presented at the final of each WP. The link between WP1-2 and WP3 is essential for the methodological aspect of the project, but while answering two distinct research questions, together they shed light on the importance of the epidemiological burden of environmental resistance in Aspergillus and its potential clinical impact as a function of its adaptive capacity. The impact of resistance traits on Aspergillus fitness cost will be investigated in environmental and host conditions to challenge the hypothesis of major clinical implication. Furthermore, while in microbiology some studies claimed that fitness cost is broadly similar in vitro and in vivo, this is not universally accepted. Resistance mutations seen in the clinical context often represent a low-cost subset of those detectable in vitro. Furthermore, fitness cost could differ with genotype implicating clinical consequences.
Resultats:
Due to the exhaustiveness of the inclusions within the pneumology department, the first expected outcome of the AspergillusOne health consortium is to identify predisposing indicators of resistance occurrence. Indeed, clinical studies are often targeted on a specific population and it is therefore difficult to know today whether a particular underlying disease is more favourable to the presence of azole-resistant aspergillus. In view of the high prevalence of azole resistance in some countries, the recommendations are to introduce amphotericin B as soon as possible despite its high nephrotoxicity. However, CYP51 mutations often affect one or a subset of azole drug compounds, and resistance across the whole class is generally incomplete. The correlation between environmental resistance mechanisms and the levels of resistance to available azole drugs will make it possible to propose personalized medicine based on the type of mutations present in the clinical isolate. On the veterinary side, the results could lead to recommendations on practices, in particular the type or origin of litters and methods of preventing its contamination. The project will allow us to build a large library (biocollection) of environmental, human and avian Aspergillus strains some of which have different resistance mechanisms for further fundamental studies. Novel susceptibility testing based on short-time drug exposure of isolates and MALDI-TOF typing as intended in this project may represent upcoming tools to survey antifungal resistance from the environment and in clinical settings. Based on the modeling expertise, we hope to be able to establish and validate the methodological basis for the identification of hotspots of aspergillus resistance which would allow extrapolation to other regions of France or to other countries where azoles are widely used in agriculture. The results obtained within the framework of this project would make it possible to adapt recommendations in fungicides uses and the regional device of pesticide monitoring in the air and water implemented by Air Pays de la Loire and the DREAL.
ANR-22-CE35-0013
